The purpose of this proposal is to develop novel inhibitors of human immunodeficiency virus (HIV replication. The initial target genes of these studies will be the nef and vif gene of HIV. The design and chemical synthesis of catalytic cleaving RNas (ribozymes) will be performed initially in solution assays, transferred to cell culture assays of efficacy and ultimately ribozymes to T lymphocytes and mononuclear cells will be developed for use in the tissue culture studies. The antiviral efficacy of ribozymes in tissue culture will be determined in collaboration with other investigators which are participants in this proposal. Tissue culture efficacy using the exogenous delivery of synthetic ribozymes as well as endogenous delivery of ribozyme transcripts from expression vectors will be judged by the reduction in specific protein production (vif and nef proteins), viral RNA and virus yield. Antiviral efficacy in the lymphocyte/monocyte systems will be determined using laboratory strains as well as recent clinical isolates of HIV. After anti-HIV efficacy has been determined, delivery protocols for animal studies will be initiated at the UCHSC facilities. The direction of the development for animal delivery vehicles will be determined by the most efficacious methods of treatment in the tissue culture experiments. We will investigate the efficacy of our candidate ribozyme molecules using HIV infections in the pig-tail macaque.